Migration and activation of microglial cells mediates a number of disease processes in the brain including neurodegenerative diseases such as those associated with Tau pathologies and Beta-amyloid diseases, CNS injuries including spinal cord injuries and traumatic brain injury (TBI) as well as neurodevelopmental disorders and conditions such as stroke, Amyotrophic lateral Sclerosis and cerebral ischemia.
There remains interest in therapeutic agents and methods for inhibiting the migration and activation of microglial cells involved in cerebral ischemia or cerebral inflammation. While the brain is considered a site of relative immune privilege there is recognition that CNS tissue injury is mediated by types of inflammatory responses including those involving microglial cells.
A traumatic brain injury (TBI) is a disruption of function in the brain that results from a blow or jolt to the head or penetrating head injury. TBI is heterogeneous in its cause and can be seen as a two-step event: 1) a primary injury, which can be focal or diffuse, caused by mechanical impact, that results in primary pathological events such as hemorrhage and ischemia, tearing of tissue and axonal injuries; 2) a secondary injury such as diffuse inflammation, cell death and gliosis, which is a consequence of the primary one. This secondary injury starts immediately after injury and can continue for weeks, and is thought to involve an active inhibition of neural stem cell activity. Collectively, these events lead to neurodegeneration.
A large fraction of TBI is mild, and thus may go undiagnosed immediately after injury. Undiagnosed and untreated TBI presents a risk because some signs and symptoms may be delayed from days to months after injury, and may have significant impact on the patient's physical, emotional, behavioral, social, or family status if untreated, and may result in a functional impairment. Because secondary damage from the injury continues after the initial impact, early treatment (and thus rapid diagnosis), particularly point-of-care treatment, is desirable. An ideal therapy for TBI would reduce the injury infarct size as well as limiting the secondary inflammatory responses. In the U.S., about 1.5 million people per year suffer a traumatic brain injury (TBI), reflecting physical damage to the brain that compromises brain function either temporarily or permanently. Of the total number so injured, some 50,000 die while another 80,000 have some degree of disability. The leading causes of TBI are accidents (auto, bicycle, pedestrian), assault, and sport-related injury.
Head injuries are described as being open or closed. Open head injuries involve penetration of the scalp and skull by bullets, sharp objects, or skull fractures resulting in laceration of brain tissue.
Closed injuries occur when rapid brain acceleration or deceleration results from shaking, crash, falls or other sudden insult. This rapid acceleration or deceleration can damage the brain at the point of contact (coup) or opposite that point (countercoup). The temporal and frontal lobes are most susceptible to damage, which can involve axon and/or blood vessel tearing. Torn blood vessels can leak and lead to hematomas, contusions, or intracerebral and subarachnoid hemorrhages.
Concussion is described as an immediate, but transient, loss of consciousness accompanied by a short period of amnesia. However, the TBI victim may appear to be dazed, disoriented or confused. A concussion may be accompanied by convulsions, hypotension, fainting and facial pallor. These signs and symptoms are usually short-lived in cases of single, uncomplicated concussion.
Traumatic brain injury can be both acute, occurring recently, as well as of the chronic form resulting from the long term consequences of such acute brain injuries including the effects of inflammation and scarring on the brain tissue.
Football and soccer players appear to suffer a significantly higher frequency of concussion than athletes in other sports. Professional football players in the National Football League (NFL) have recently brought to the public's attention the long-term consequences of multiple concussions incurred during their playing days. Included as frequently reported signs are loss of cognition, decreased communicative skills, compromised emotional stability, poor coordination, memory loss and dementia.
An increasingly prevalent subset of TBI is blast-induced or blast TBI (bTBI). With the increasing use of explosives, including improvised explosive devices (IEDs) in the global war on terrorism, bTBI is also increasing. Such injuries are often referred to as the hallmark injury of the wars in Iraq and Afghanistan, and affect both military and civilian workers in battle zones. Blast injuries are the most common cause of TBI in US soldiers in combat and a major cause of disability among service members.
Blast injuries can result in the full spectrum of closed and penetrating TBIs (mild, moderate, and severe). Mild and moderate TBI's are more prevalent than severe injuries in the current military conflict due to the vast improvement in protective gear, leading to an increase in survivors of bTBI.
Blast injuries are defined by four potential mechanism dynamics: (1) Primary Blast Atmospheric over-pressure followed by under-pressure or vacuum; (2) Secondary Blast Objects placed in motion by the blast hitting the subject; (3) Tertiary Blast: Subject being placed in motion by the blast and (4) Quaternary Blast: Other injuries from the blast such as burns, crush injuries, amputations, toxic fumes.
bTBI are typically closed-head injuries and are more complex than other forms of TBI, with multiple mechanisms of injury including shockwave transmission through the skull and sensory organs of the head. In a patient sample seen in the Department of Veterans Affairs (VA) polytrauma system, the pattern of injuries was different among those with injuries due to blasts versus other mechanisms. Injuries to the face (including eye, ear, oral, and maxillofacial), penetrating brain injuries, symptoms of posttraumatic stress, and auditory impairments are more common in blast-injured patients than in those with war injuries of other etiologies. Sayer N A et al. (2008) Arch Phys Med. Rehabil. January; 89:163-70. Accordingly there remains an interest in therapies which might be effective in treating one or more symptoms of both acute and chronic traumatic brain injury.
Related to but not limited to traumatic brain injuries are hematomas in the brain. Hematomas are broadly defined as collections of blood outside of blood vessels and when they occur in the brain they are associated with the activation and migration of microglial cells to the location of the injury.
Streptolysin O (SLO) is one of a group of filterable hemolysins derived from Group A beta-hemolytic streptococci. Specifically, streptolysin O is a 60-kD peptide, which is hemolytic in its reduced state, but is inactivated upon oxidation (Johnson et al., Infect. Immun., 27:97-101, 1980; Alouf et al., Pharmacol. Ther., 3:661-717, 1984; Bhakdi et al., Infect. Immun., 47:52-60, 1985, the disclosures of which are incorporated herein by reference in their entirety). Group A streptococci produce streptolysin O. Streptolysin O is used in the art generally as an analytical reagent for permeabilizing cells (e.g. Razin et al., Proc. Nat'l. Acad. Sci. (USA) 91:7722-7726 (1994).
Of interest to the present invention are the disclosures of co-owned U.S. Pat. Nos. 5,576,289 and 5,736,508 which are hereby incorporated by reference. U.S. Pat. No. 5,576,289 discloses the use of streptolysin O in methods for treating disease states characterized by motor deficit including multiple sclerosis and autism. U.S. Pat. No. 5,736,508 discloses the use of streptolysin O in methods for treating scarring.
Of further interest to the present invention are the disclosures in co-owned U.S. Pat. Nos. 7,196,058 and 7,629,058 the disclosures of which are incorporated by reference herein which disclose streptolysin O as having effects on MMP-2 which is a keratinocyte cell surface marker and is believed to be involved in the breakdown of extracellular matrix in normal physiological processes. Keratinocyte migration is involved in wound healing.